Suicide is the second leading cause of death worldwide among females of reproductive age, yet we are unable to reliably predict when suicide attempts will occur. Perimenstrual (around menses) withdrawal from the ovarian steroids estradiol (E2) and progesterone (P4) correlates with suicidal behavior and therefore may represent a time-varying predictor of acute risk for suicidal ideation and behavior. K99 Results: The linked K99 award has provided the first experimental evidence that perimenstrual E2/P4 withdrawal (vs. experimental stabilization) withdrawal causes acute worsening of suicidality among females. In a sample of 30 females with recent suicidality completing a double-blind, placebo-control crossover trial of perimenstrual E2/P4 stabilization (vs. natural withdrawal under placebo), exogenous hormone stabilization prevented perimenstrual exacerbation of task, self-report, and interview-based indices of acute suicide risk. R00 Research Question: The critical next step of this research program (R00) is to clarify whether E2 withdrawal, P4 withdrawal, or some combination are responsible for the perimenstrual exacerbation of suicidality observed among at-risk women. Further, it is necessary to determine whether withdrawal from the neurosteroid metabolites of P4 (e.g., allopregnanolone) might account for the influence of ovarian steroid hormone withdrawal on suicidality. R00 Design: The proposed R00 experiment will recruit a similar sample of 30 women with past-month suicidality and utilize an expanded crossover design to compare perimenstrual exacerbation of suicide risk across three counterbalanced, double-blind conditions: (1) perimenstrual administration of placebo only (natural perimenstrual withdrawal from E2/P4), (2) perimenstrual stabilization of E2 only (natural withdrawal from P4 only), and (3) perimenstrual stabilization of P4 only (natural withdrawal from E2 only). Suicidality and mediating behavioral constructs will be measured daily and at three laboratory visits across each condition. Weekly steroids (E2, P4) and a panel of neuroactive GABAergic neurosteroids (including P5, PREGS, 3?-5?- THP, 3?-5?-THP) will also be measured via RIA or GC-MS in serum collected at each lab. Specific Aims: (1) Test the hypothesis that, compared to P4 stabilization, P4 withdrawal (in both the placebo condition and the E2 stabilization condition) will exacerbate suicidality by altering four suicide-relevant constructs toward risk (hopelessness, negative social appraisal, poor inhibitory control, and threat sensitivity); and (2) Test the hypothesis that this P4 stabilization will prevent perimenstrual increases in suicidality and associated constructs (relative to P4 withdrawal conditions) by stabilizing perimenstrual GABAergic neurosteroids. Research Team: A team of experts from the University of North Carolina at Chapel Hill (UNC) and the University of Illinois at Chicago (UIC) will continue to provide support and consultation to the PI during the R00. Susan Girdler, Ph.D. (UNC) and David Rubinow, M.D. (UNC) will continue to provide consultation regarding best practices for safe ovarian hormone manipulation and neurosteroid mechanisms in psychiatric samples. Mitch Prinstein, Ph.D. (UNC) will continue to provide clinical consultation regarding the assessment and management of acute suicide risk in the context of clinical research. Luan Phan, M.D. (UIC) will coordinate medical oversight (prescription of hormones, physical risk management) of the R00 at UIC. Future Directions and